AKTIP/Ft1, a New Shelterin-Interacting Factor Required for Telomere Maintenance

English version České info

Chromosome ends are capped by specialized structures called telomeres, which protect chromosomes from deterioration, incomplete replication and end-to-end fusion. Defects in telomere structure and/or function may have a strong impact on human health, leading to premature aging and a variety of diseases including cancer. One of the most important tasks to understand and possibly prevent the consequences of telomere dysfunction is the identification and characterization of telomere-associated proteins. Here we show for the first time that human telomeric proteins can be identified on the basis of their homology with those that protect the telomeres of the fruit fly Drosophila melanogaster. Although flies and humans elongate their telomeres through different mechanisms, our studies suggested that a subset of Drosophila telomere-associated proteins have conserved human counterparts. Based on this hypothesis we identified and characterized a novel human telomeric protein called AKTIP. We show that AKTIP binds the components of the shelterin multiprotein complex, which caps and protects the human telomeres. AKTIP-depleted chromosomes exhibit an accumulation of DNA repair factors at their ends (telomere dysfunction foci), which are diagnostic of telomere damage. Loss of AKTIP results in a general impairment of DNA synthesis and in defective telomere replication. Collectively, our results indicate that AKTIP cooperates with the shelterin component TRF1 to ensure proper telomere replication.

Vyšlo v časopise: AKTIP/Ft1, a New Shelterin-Interacting Factor Required for Telomere Maintenance. PLoS Genet 11(6): e32767. doi:10.1371/journal.pgen.1005167
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1005167

Souhrn

Zdroje

1. Blackburn E, Greider C, Szostak J. Telomeres and telomerase: the path from maize, Tetrahymena and yeast to human cancer and aging. Nat Med. 2006;12(10):1133–8. 17024208

2. Palm W, de Lange T. How shelterin protects mammalian telomeres. Ann Rev Genet. 2008;42:301–34. doi: 10.1146/annurev.genet.41.110306.130350 18680434

3. Hockemeyer D, Sfeir A, Shay J, Wright W, de Lange T. POT1 protects telomeres from a transient DNA damage response and determines how human chromosomes end. Embo J. 2005;24(14):2667–78. 15973431

4. Hockemeyer D, Palm W, Else T, Daniels J, Takai K, Ye J, et al. Telomere protection by mammalian Pot1 requires interaction with Tpp1. Nat Struct Mol Biol. 2007;14(8):754–61. 17632522

5. Denchi E, de Lange T. Protection of telomeres through independent control of ATM and ATR by TRF2 and POT1. Nature. 2007;448:1068–71. 17687332

6. Sfeir A, Kosiyatrakul ST, Hockemeyer D, MacRae SL, Karlseder J, Schildkraut CL, et al. Mammalian telomeres resemble fragile sites and require TRF1 for efficient replication. Cell. 2009;138(1):90–103. doi: 10.1016/j.cell.2009.06.021 19596237

7. Martínez P, Thanasoula M, Muñoz P, Liao C, Tejera A, McNees C, et al. Increased telomere fragility and fusions resulting from TRF1 deficiency lead to degenerative pathologies and increased cancer in mice. Genes Dev. 2009;23(17):2060–75. doi: 10.1101/gad.543509 19679647

8. Jain D, Cooper J. Telomeric strategies: means to an end. Annu Rev Genet 2010;44:243–69. doi: 10.1146/annurev-genet-102108-134841 21047259

9. Surovtseva Y, Churikov D, Boltz K, Song X, Lamb J, Warrington R, et al. Conserved telomere maintenance component 1 interacts with STN1 and maintains chromosome ends in higher eukaryotes. Mol Cell. 2009;36(2):207–18. doi: 10.1016/j.molcel.2009.09.017 19854131

10. Miyake Y, Nakamura M, Nabetani A, Shimamura S, Tamura M, Yonehara S, et al. RPA-like mammalian Ctc1-Stn1-Ten1 complex binds to single-stranded DNA and protects telomeres independently of the Pot1 pathway. Mol Cell. 2009;23(2):193–206.

11. Leman AR, Dheekollu J, Deng Z, Lee SW, Das MM, Lieberman PM, et al. Timeless preserves telomere length by promoting efficient DNA replication through human telomeres. Cell Cycle. 2012;11(12):2337–47. doi: 10.4161/cc.20810 22672906

12. Kasbek C, Wang F, Price CM. Human TEN1 maintains telomere integrity and functions in genome-wide replication restart. J Biol Chem. 2013;288(42):30139–50. doi: 10.1074/jbc.M113.493478 24025336

13. Vannier J, Pavicic-Kaltenbrunner V, Petalcorin M, Ding H, Boulton S. RTEL1 Dismantles T Loops and Counteracts Telomeric G4-DNA to Maintain Telomere Integrity. Cell. 2012;149(4):795–806. doi: 10.1016/j.cell.2012.03.030 22579284

14. van Overbeek M, de Lange T. Apollo, an Artemis-related nuclease, interacts with TRF2 and protects human telomeres in S phase. Curr Biol. 2006;16(13):1295–302. 16730176

15. Lam YC, Akhter S, Gu P, Ye J, Poulet A, Giraud-Panis MJ, et al. SNMIB/Apollo protects leading-strand telomeres against NHEJ-mediated repair. Embo J. 2010;29(13):2230–41. doi: 10.1038/emboj.2010.58 20551906

16. Wu P, van Overbeek M, Rooney S, de Lange T. Apollo contributes to G overhang maintenance and protects leading-end telomeres. Mo Cell. 2010;39(4):606–17. doi: 10.1016/j.molcel.2010.06.031 20619712

17. Ye J, Lenain C, Bauwens S, Rizzo A, Saint-Leger A, Poulet A, et al. TRF2 and apollo cooperate with topoisomerase 2alpha to protect human telomeres from replicative damage. Cell. 2010;142(2):230–42. doi: 10.1016/j.cell.2010.05.032 20655466

18. Gu P, Min J, Wang Y, Huang C, Peng T, Chai W, et al. CTC1 deletion results in defective telomere replication, leading to catastrophic telomere loss and stem cell exhaustion. EMBO J. 2012;31(10):2309–21. doi: 10.1038/emboj.2012.96 22531781

19. Stewart JA, Wang F, Chaiken MF, Kasbek C, Chastain PD 2nd, Wright WE, et al. Human CST promotes telomere duplex replication and general replication restart after fork stalling. Embo J. 2012;31(17):3537–49. doi: 10.1038/emboj.2012.215 22863775

20. Cenci G, Ciapponi L, Marzullo M, Raffa G, Morciano P, Raimondo D, et al. The analysis of pendolino (peo) mutants reveals differences in the fusigenic potential among Drosophila telomeres. PLoS Genetics. 2015;11(6).

21. Raffa GD, Siriaco G, Cugusi S, Ciapponi L, Cenci G, Wojcik E, et al. The Drosophila modigliani (moi) gene encodes a HOAP-interacting protein required for telomere protection. Proc Natl Acad Sci U S A. 2009;106(7):2271–6. doi: 10.1073/pnas.0812702106 19181850

22. Raffa G, Ciapponi L, Cenci G, Gatti M. Terminin: a protein complex that mediates epigenetic maintenance of Drosophila telomeres. Nucleus. 2011;2(5):383–91. doi: http://dx.doi.org/10.4161/nucl.2.5.17873 21989238

23. Raffa G, Raimondo D, Sorino C, Cugusi S, Cenci G, Cacchione S, et al. Verrocchio, a Drosophila OB fold-containing protein, is a component of the terminin telomere-capping complex. Genes Dev. 2010;24(15):1596–601. doi: 10.1101/gad.574810 20679394

24. Harper JW, Elledge SJ. The DNA damage response: ten years after. Mol Cell. 2007;28(5):739–45. 18082599

25. Rinn JL, Huarte M. To repress or not to repress: this is the guardian's question. Trends Cell Biol. 2011;21(6):344–53. doi: 10.1016/j.tcb.2011.04.002 21601459

26. Takai H, Smogorzewska A, de Lange T. DNA damage foci at dysfunctional telomeres. Curr Biol. 2003;13(17):6533–41.

27. Remy I, Michnick S. Regulation of apoptosis by the Ft1 protein, a new modulator of protein kinase B/Akt. Mol Cell Biol. 2004;24(4):1493–504. 14749367

28. Xu L, Sowa M, Chen J, Li X, Gygi S, Harper J. An FTS/Hook/p107(FHIP) complex interacts with and promotes endosomal clustering by the homotypic vacuolar protein sorting complex. Mol Biol Cell 2008;19(12):5059–71. doi: 10.1091/mbc.E08-05-0473 18799622

29. Ye Y, Rape M. Building ubiquitin chains: E2 enzymes at work. Nat Rev Mol Cell Biol 2009;10(11):755–64. doi: 10.1038/nrm2780 19851334

30. Moldovan GL, Pfander B, Jentsch S. PCNA, the maestro of the replication fork. Cell. 2007;129(4):665–79. 17512402

31. Mailand N, Gibbs-Seymour I, Bekker-Jensen S. Regulation of PCNA-protein interactions for genome stability. Nature reviews Molecular cell biology. 2013;14(5):269–82. doi: 10.1038/nrm3562 23594953

32. Chagin V, Stear J, Cardoso M. Organization of DNA replication. Cold Spring Harb Perspect Biol 2010;2(2):a000737. doi: 10.1101/cshperspect.a000737 20452942

33. Dimitrova D, Berezney R. The spatio-temporal organization of DNA replication sites is identical in primary, immortalized and transformed mammalian cells. J Cell Sci. 2002;115(21):4037–51. 12356909

34. Arnoult N, Schluth-Bolard C, Letessier A, Drascovic I, Bouarich-Bourimi R, Campisi J, et al. Replication timing of human telomeres is chromosome arm-specific, influenced by subtelomeric structures and connected to nuclear localization. PLoS genetics. 2010;6(4):e1000920. doi: 10.1371/journal.pgen.1000920 20421929

35. Yonekawa T, Yang S, Counter C. PinX1 localizes to telomeres and stabilizes TRF1 at mitosis. Mol Cell Biol 2012;32(8):1387–95. doi: 10.1128/MCB.05641-11 22331467

36. Zhu X, Küster B, Mann M, Petrini J, de Lange T. Cell-cycle-regulated association of RAD50/MRE11/NBS1 with TRF2 and human telomeres. Nat Genet. 2000;25(3):347–52. 10888888

37. Hurley JH, Lee S, Prag G. Ubiquitin-binding domains. The Biochemical journal. 2006;399(3):361–72. 17034365

38. Jiang Y, Ou Y, Cheng X. Role of TSG101 in cancer. Frontiers in bioscience. 2013;18:279–88. 23276921

39. Gao G, Walser J, Beaucher M, Morciano P, Wesolowska N, Chen J, et al. HipHop interacts with HOAP and HP1 to protect Drosophila telomeres in a sequence-independent manner. EMBO J. 2010;29(4):819–29. doi: 10.1038/emboj.2009.394 20057353

40. O'Sullivan R, Karlseder J. Telomeres: protecting chromosomes against genome instability. Nat Rev Mol Cell Biol 2010;11(3):171–81. doi: 10.1038/nrm2848 20125188

41. Novo C, Arnoult N, Bordes WY, Castro-Vega L, Gibaud A, Dutrillaux B, et al. The heterochromatic chromosome caps in great apes impact telomere metabolism. Nucleic acids research. 2013;41(9):4792–801. doi: 10.1093/nar/gkt169 23519615

42. Cerone M, Marchetti A, Bossi G, Blandino G, Sacchi A, Soddu S. p53 is involved in the differentiation but not in the differentiation-associated apoptosis of myoblasts. Cell Death Diff. 2000;7:506–8.

43. Piersanti S, Sacchetti B, Funari A, Di Cesare S, Bonci D, Cherubini G, et al. Lentiviral transduction of human postnatal skeletal (stromal, mesenchymal) stem cells: in vivo transplantation and gene silencing. Calcif Tissue Int. 2006;78(6):372–84. 16830199

44. van Steensel B, Smogorzewska A, de Lange T. TRF2 protects human telomeres from end-to-end fusions. Cell. 1998;6(92):401–13.

45. Ijdo J, Wells R, Baldini A, Reeders S. Improved telomere detection using a telomere repeat probe (TTAGGG)n generated by PCR. Nucleic Acids Res 1991;19(17):4780. 1891373

46. Amiard S, Doudeau M, Pinte S, Poulet A, Lenain C, Faivre-Moskalenko C, et al. A topological mechanism for TRF2-enhanced strand invasion. Nat Struct Mol Biol 2007;14(2):147–54. 17220898

47. Galati A, Magdinier F, Colasanti V, Bauwens S, Pinte S, Ricordy R, et al. TRF2 controls telomeric nucleosome organization in a cell cycle phase-dependent manner. PLoS One. 2012;7(4):e34386. doi: 10.1371/journal.pone.0034386 22536324

48. Roy A, Kucukural A, Zhang Y. I-TASSER: a unified platform for automated protein structure and function prediction. Nat Protoc. 2010;5(4):725–38. doi: 10.1038/nprot.2010.5 20360767

49. Li Y, Roy A, Zhang Y. HAAD: A quick algorithm for accurate prediction of hydrogen atoms in protein structures. PLoS One 2009;4(8):e6701. doi: 10.1371/journal.pone.0006701 19693270

50. Zhang J, Liang Y, Zhang Y. Atomic-level protein structure refinement using fragment-guided molecular dynamics conformation sampling. Structure. 2011;19(12):1784–95. doi: 10.1016/j.str.2011.09.022 22153501

51. Wallner B, Elofsson A. Identification of correct regions in protein models using structural, alignment, and consensus information. Protein Sci. 2006;15(4):900–13. 16522791

52. Benkert P, Biasini M, Schwede T. Toward the estimation of the absolute quality of individual protein structure models. Bioinformatics. 2011;27(3):343–50. doi: 10.1093/bioinformatics/btq662 21134891